The purpose of this proposal is to launch the independent research career of an interventional cardiologist who wishes to focus on identifying novel molecular mechanisms underlying arterial repair and atherosclerosis. The overall scientific aim is to provide important insights towards deriving targeted strategies to fight cardiovascular disease. To achieve this, the Candidate will couple training in a range of molecular and cell profiling techniques with a structured program of career developmental activities. The Candidate will be supervised by a dedicated team of mentors and advisors who will oversee the proposed research project and career development program. There has been a paucity of significant breakthroughs in our understanding of vascular disease and atherosclerosis in recent years. While incremental progress has been made, the field continues to search in earnest for ways to stabilize atherosclerotic plaques and reduce cardiovascular disease. Given that atherothrombosis remains the #1 killer in Western society, this is an urgent and unmet clinical need. Founded upon on compelling preliminary data, this proposal is a two-pronged systematic approach to address this problem. The role of the endothelium and of endothelial to mesenchymal cell transition in normal vascular biology and atherosclerosis is the focal point of this proposal. In Specific Aim 1, using unique mouse models to track endothelial cells as they migrate and even change their phenotype, the Candidate will characterize key cell types and identify new molecular pathways responsible for endothelial homeostasis and repair. These are critical questions to address, as the failure to properly repair the endothelium leads to arterial thrombosis, vascular occlusion and tissue death. In Specific Aim 2, focused and detailed experiments will explore the cellular and molecular processes that underpin atherosclerosis. Specifically, the Candidate will investigate the ability of endothelial cells to switch their celluar phenotype to become smooth muscle cells, fibroblasts or other cells that drive atherosclerosis. This project will define the extent of this 'cell switching' and will unlock ways to manipulate thi process with the goal of developing novel and more efficacious treatment options. In addition, these experiments will be used to train the Candidate in the techniques of laser-capture microdissection, gene chip analysis, flow cytometry and the use of viral vectors. This program will serve as the seed for future molecular studies and also for potential pre-clinical and ultimately clinical studies targeting atherosclerosis and vascular disease. The relevance of this project to clinical medicine and society is significant. Here, we will investigate the cellular and molecular mechanisms dictating cardiovascular morbidity and mortality, with a view to making meaningful inroads into the prevention and treatment of this epidemic. PUBLIC HEALTH RELEVANCE: This proposal seeks to characterize the contribution of endothelial cells to arterial homeostasis, arterial repair and atherosclerosis. Using unique mouse models we will define the function of endothelial cells in these processes and also investigate the ability of endothelial cells to change their phenotype to become smooth muscle cells, fibroblasts or other cells that drive atherosclerosis. These experiments are highly relevant to public health as they are designed to identify novel molecular pathways, with the ultimate aim of creating new treatments to fight cardiovascular disease.